Melanocyte stimulating hormones (MSH) derived from pro-opiomelanocortin have been demonstrated to participate in the central regulation of cardiovascular functions. The aim of the present study was to elucidate the chronic effects of increased melanocortin activation on blood pressure regulation and autonomic nervous system function. We adapted telemetry to transgenic mice overexpressing alpha- and gamma-MSH and measured blood pressure, heart rate and locomotor activity, and analyzed heart rate variability (HRV) in the frequency-domain as well as baroreflex function by the sequence technique. Transgenic (MSH-OE) mice had increased systolic blood pressure but their heart rate was similar to wild-type (WT) controls. The 24-h mean of systolic blood pressure was 132+/-7mmHg in MSH-OE and 113+/-4mmHg in WT mice. Locomotor activity was decreased in the MSH-OE mice. Furthermore, MSH-OE mice showed slower adaptation to mild environmental stress in terms of blood pressure changes. The low frequency (LF) power of HRV tended to be higher in MSH-OE mice compared to WT mice, without a difference in overall variability. The assessment of baroreflex function indicated enhanced baroreflex effectiveness and more frequent baroreflex operations in MSH-OE mice. Baseline heart rate, increased LF power of HRV and increased baroreflex activity may all reflect maintenance of baroreflex integrity and an increase in cardiac vagal activity to counteract the increased blood pressure. These results provide new evidence that long-term activation of the melanocortin system elevates blood pressure without increasing heart rate.